Dissertation
Biomimetic proteoglycans molecularly engineer cartilage pericellular matrix and can be leveraged as a multi-functional drug delivery platform
Doctor of Philosophy (Ph.D.), Drexel University
May 2023
DOI:
https://doi.org/10.17918/00001689
Abstract
Osteoarthritis (OA) is the most common cause of disability in older adults, afflicting an estimated 10-15% of adults aged over 60. In early OA, degeneration of cartilage pericellular matrix (PCM), a 2-4 [mu]m thick region surrounding chondrocytes that facilitates cross-talk between the extracellular matrix (ECM) and chondrocytes in the process of mechanotransduction, is one leading event of disease initiation. Controlled, in part, by an inflammatory response of catabolic enzymes, critical biomolecules of the PCM, such as proteoglycans, are early casualties of the disease resulting in reduced PCM micromodulus, abnormal cellular mechanotransduction, and a corresponding increase in a catabolic metabolism. Successful regeneration of degraded OA cartilage has been challenged by our limited capability of regenerating the biomechanical and biophysical cross-talk between the ECM and chondrocytes. This renders the pericellular matrix (PCM), the immediate chondrocyte microniche, an emerging target for modulating chondrocyte mechanotransduction in both healthy and OA cartilage. This thesis utilizes the biomimetic proteoglycan BPG10, which has a "bottle-brush"-like nanoarchitecture mimicking the native proteoglycan aggrecan, and is comprised of 7-8 chondroitin sulfate glycosaminoglycan chains chemically attached to a poly(acrylic acid) core (MW ~10 kDa). When infiltrated into bovine cartilage explants ex vivo, BPG10 diffused throughout the matrix and was preferentially localized in the PCM. Distribution, association, and retention of BPG10 in cartilage PCM in vivo and ex vivo was shown to be possible through adhesive inter-molecular interactions with a PCM predominant, native proteoglycan, aggrecan. This localization led to increased PCM micromodulus, and in turn, significantly enhanced chondrocyte intracellular calcium signaling activities, a marker of mechanotransduction. When infiltrated into both human OA and normal cartilage, BPG10 also localized in the PCM to a varying degree and mechanically enhanced this cellular microniche, indicating a translational potential for BPGs to restore degenerative PCM mechanics and rescue disrupted chondrocyte mechanosensitive activities. Given its capability of localizing in the PCM, BPG10 was thus leveraged as a drug delivery platform for the potential disease modifying OA drug (DMOAD) dexamethasone to increase its therapeutic efficacy while simultaneously providing mechanical and mechanobiological support to the PCM. Through the combination of local delivery of dexamethasone and mechanical reinforcement of the cellular microniche via BPG10, the degree of cartilage degradation was ameliorated in an ex vivo inflammatory cartilage model by the BPG10-drug constructs. Collectively, these outcomes have provided a new path for molecular engineering of cartilage pericellular matrix and attenuation of disease progression in OA.
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Details
- Title
- Biomimetic proteoglycans molecularly engineer cartilage pericellular matrix and can be leveraged as a multi-functional drug delivery platform
- Creators
- Elizabeth Kahle
- Contributors
- Lin Han (Advisor)Michele Marcolongo (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xv, 131 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems (1997-2026); Drexel University
- Other Identifier
- 991020876809104721